Complications of Tyrosine Kinase Inhibitors Therapy in Chronic Myeloid Leukemia-Chronic Phase

DESPINA CALAMAR POPOVICI1,2#, IOANA IONITA1,3*, MIRELA NEDELCU2 , CLAUDIU IONITA3,4#, HORTENSIA IONITA1, RADU DUMITRU MOLERIU5, CALIN OVIDIU ILIE6#, DANIELA IACOB7, LUCA TUDOR CONSTANTIN8*, ADELINA CHEVERESAN9*, DELIA BERCEANU VADUVA9*, DANIELA RADU10 1University of Medicine and Pharmacy Victor Babes Timisoara, Department of Hematology, 2 Eftimie Murgu Sq., 300041,Timisoara, Romania 2City Clinical Emergency Hospital, Hematology Clinic, 1 Hector Str., 300041,Timisoara, Romania 3University of Medicine and Pharmacy Victor Babes Timisoara, Department of Surgery, 2 Eftimie Murgu Sq., 300041,Timisoara, Romania 4City Clinical Emergency Hospital, Surgery Clinic,1 Hector Str., 300041, Timisoara, Romania 5 West University of Timisoara, Faculty of Mathematics and Computer Science, Department of Mathematics, 4 Vasile Parvan Blvd., 300223,Timisoara, Romania 6University of Medicine and Pharmacy Victor Babes Timisoara, Faculty of Dental Medicine, Discipline of Dental Technology, 2 Eftimie Murgu Sq., 300041,Timisoara, Romania 7University of Medicine and Pharmacy Victor Babes Timisoara, Department of Neonatology, 2 Eftimie Murgu Sq., 300041,Timisoara, Romania 8University of Medicine and Pharmacy Victor Babes Timisoara, Department of Cardiology, 2 Eftimie Murgu Sq., 300041,Timisoara, Romania 10University of Medicine and Pharmacy Victor Babes Timisoara, Faculty of Medicine, 2 Eftimie Murgu Sq., 300041,Timisoara, Romania 10University of Medicine and Pharmacy Victor Babes Timisoara, Department Surgery, 2 Eftimie Murgu Sq., 300041,Timisoara, Romania

Chronic myeloid leukemia was treated throughout its history with Busulfan or Hydroxyurea and presented a poor prognosis. These agents have controlled hematologic manifestations but have not delayed disease progression. Imatinib, a small molecule tyrosine kinase inhibitor, was first generation of drugs that target BCR-ABL and became the standard first-line therapy in chronic phase of CML.
Subsequently emerged second generation molecules, following the strategies used to overcome resistance to Imatinib. These include new drugs, more powerful like Dasatinib and Nilotinib. These three molecules being surveyed in this paper. The most common side effects of treatment with Imatinib are haematological: neutropenia, thrombocytopenia, anemia, while in the case of Dasatinib most frequent complications are pleural effusion and dyspnea. Nilotinib shows that common side effects neutropenia and thrombocytopenia [1][2].
This paper aims to assess complications of therapy with tyrosine kinase inhibitors in chronic phase of chronic myeloid leukemia and establishing correlations with the type of inhibitor used.

Experimental part Material and methods
The study was performed on a total of 140 patients diagnosed with chronic phase CML in the Hematology Department of the City Clinical Emergency Hospital Timisoara between January 2006 -January 2016.
The database includes anthropometric data and results of laboratory investigations, types of inhibitors used and complications occurred after their administration. Data presented in percentage and comparisons between groups were made Oneway Anowa [3][4][5].

Results and discussions
The group included a total of 140 patients, of which 57 (40.72%) were female and 83 (59.28%) were males. The ratio B / F is 1.45 for male. The age was between 23 and 82 years. The average age was 52.16 years. The patients were divided into three age groups, namely : 20-30 years, 31-50 years and over 50 years. The distribution of patients by age and sex is shown in Table 1. We can see that in the age group 20 to 30 entered a total of 7 patients (5%), of which * email: mdioanaionita@yahoo.com, Phone: 0723539800; ctluca@cardiologie.ro, Phone: 0744549340; adedent73@gmail.com; berceanu.delia@umft.ro 3 were women and 4 men, in the group 31 -50 years we have 44 patients (31.43%) of which 15 women and 29 men, and 50 years group, 89 patients (63.57%) of which 39 were women and 50 were men.
Female gender in the age group over 50 years of age has a number of premenopausal, menopausal disorders that alter daily activities. The increased incidence of malignant pathology in the genital area (uterine cancer, breast) at this age, as well as cardiovascular pathology are more and more common clinical diagnoses [6][7][8][9][10][11][12][13][14][15].
There were analyzed few important parameters in clinical and laboratory diagnosis of chronic phase in chronic myeloid leukemia. All the data are shown in Table 2. The distribution of patients according to the type of tyrosine kinase inhibitors used in the treatment of the patients in our study group is shown in Table 3.
To assess complications presented in the Table 4 were performed for all patients complete and extensive biochemical tests, ECG, cardiac ultrasound, and very thorough case history.
The frequency of complications in the studied group is different depending on the type of tyrosine kinase inhibitors used. As seen from the above table for Imatinib, the most common complications were neutropenia, anemia, thrombocytopenia, while for patients treated with Dasatinib the most frequent were hidric retention, chest pain, pulmonary arterial hypertension, heart problems .

Conclusions
Patients with chronic myeloid leukemia develop numerous complications that differ depending on the type of tyrosine kinase inhibitor used. What is important to note is that all types of inhibitors occur in a higher percentage of haematological complications as seen in Table 4: Anemia, neutropenia, thrombocytopenia. The importance of these complications has been studied in many clinical trials both in the United States and the UK, and is mainly related to the need to discontinue treatment until normalization of hemogram values [18][19][20].
This study reveals that depending on the type of tyrosine kinase inhibitors, the most frequently occurring complications vary but there are some haematological changes that persist in a large number of patients regardless of the inhibitor used.
Despite these inconveniences, modern ITK therapy significantly improves both survival and quality of life for patients.